Straightforward synthesis of complex polymeric architectures with ultra-high chain density

Synthesis of complex polymeric architectures (CPAs) via reversible-deactivation radical polymerization (RDRP) currently relies on the rather inefficient attachment of monofunctional initiation/transfer sites onto CPA precursors. This drawback seriously limits the overall functionality of the resulting (macro)initiators and, consequently, also the total number of installable polymeric chains, which represents a significant bottleneck in the design of new polymeric materials. Here, we show that the (macro)initiator functionality can be substantially amplified by using trichloroacetyl isocyanate as a highly efficient vehicle for the rapid and clean introduction of trichloroacetyl groups (TAGs) into diverse precursors. Through extensive screening of polymerization conditions and comprehensive NMR and triple-detection SEC studies, we demonstrate that TAGs function as universal trifunctional initiators of copper-mediated RDRP of different monomer classes, affording low-dispersity polymers in a wide molecular weight range. We thus unlock access to a whole new group of ultra-high chain density CPAs previously inaccessible via simple RDRP protocols. We highlight new opportunities in CPA synthesis through numerous examples, including the de novo one-pot synthesis of a novel “star-on-star” CPA, the preparation of β-cyclodextrin-based 45-arm star polymers, and facile grafting from otherwise problematic cellulose substrates both in solution and from surface, obtaining effortlessly ultra-dense, ultra-high-molecular weight bottle-brush copolymers and thick spatially-controlled polymeric coatings, respectively.


Introduction
Complex polymeric architectures (CPAs), such as star, 1 dendrimer, 2 gra, 3 bottle-brush, 4 or hyperbranched 5 (co)polymers, are characterized by an additional layer of intricacy endowing these polymeric objects with unique physical properties and an ability to self-assemble into higher-order structures.][18] Reversible-deactivation radical polymerization (RDRP) methods, and particularly copper-mediated RDRP (Cu-RDRP) and reversible addition-fragmentation chain transfer (RAFT), represent powerful tools for precisely controlling composition, functionality, and topology of polymeric chains, enabling thus a straightforward access to unique CPAs otherwise unattainable with conventional polymerization techniques. 19,20In the key step of CPA synthesis via RDRP, a CPA precursor is decorated with specic functionalities, such as initiators in Cu-RDRP or transfer agents in RAFT, that predetermine the sites of the future polymer chain attachment or growth.The concentration and distribution of these sites within the precursor is essential for determining key CPA characteristics, such as graing density in gra copolymers or the number of arms in star polymers, and thus the (co)polymer's macroscopic properties and application prospects. 3Importantly, the current implementation of the RDRP strategy operates almost exclusively with monofunctional initiation/transfer sites, allowing for a maximum of one polymeric chain per site.Unfortunately, this inherent limitation is oen further exacerbated by the inefficiency of the reactions used for the initiation/transfer site attachment and by the decreased initiation efficiency (IE) observed in some Cu-RDRP systems. 21Collectively, these shortcomings impose signicant limitations on the total number of polymeric chains that could be installed onto a given CPA precursor, which is detrimental in applications relying on high graing density 14,22 and generally represents a clear bottleneck in macromolecular design.
Cu-RDRP can potentially provide an elegant solution to some of these drawbacks in the form of multifunctional initiation sites.In multifunctional Cu-RDRP initiators (e.g., CCl 4 or a-di/ trichloro esters), more than one of the present carbon-halogen bonds can theoretically undergo activation by a copper catalyst, initiating the growth of multiple polymeric chains from a single carbon atom.In the case of CPA synthesis, bi-or trifunctional initiation sites could possibly be employed, providing instantaneous amplication of the functionality of the precursor-derived (macro)initiator.7][28][29][30] A rare example of multifunctional Cu-RDRP initiator usage in CPA synthesis was the graing from cellulose esters decorated with bifunctional dichloroacetate initiation sites reported by Vlček et al. 31,32 However, while these pioneering efforts resulted in a comparatively higher graing density, they suffered from two serious limitations.Firstly, the dichloroacetate initiator lacked universality, being successfully used for methacrylates only.More importantly, the graing density was still seriously diminished by the typical inefficiency of the initiation site attachment that traditionally relies on the acylation of precursor's hydroxyl or amino groups with an ahaloacyl halide, whereby only relatively little initiator is oen introduced despite using a large excess of the acylation reagent. 14,31,33,34While this issue is also relevant to smallmolecule CPA precursors, 34 it is particularly pronounced for macromolecular substrates such as cellulose where the supramolecular structure signicantly diminishes the acylation efficiency, 14,30,33 necessitating the development of elaborate, multistep strategies to prepare densely-graed products. 14Furthermore, the standard acylation protocols generate byproducts that need to be removed in a separate step via recrystallization/ chromatography (for small molecules) [34][35][36] or precipitation/ extraction (for macromolecular precursors). 14,32,33,37In addition, long reaction times ranging from several hours up to a week are typically used in these transformations. 13,14,35,38ollectively, the described limitations have so far prevented the macromolecular community from exploiting the full potential of multifunctional Cu-RDRP initiating sites in CPA synthesis.
Clearly, several criteria have to be met in order to successfully amplify the (macro)initiator functionality through multifunctional Cu-RDRP initiation sites and enable thus the synthesis of CPAs with a severalfold higher number of polymeric chains as compared to current protocols.Firstly, the multifunctional initiation sites must be sufficiently universal, that is, applicable to different monomer classes, ideally under diverse polymerization conditions.Further, the IE should be sufficiently high with respect to both the entire (macro)initiator and the individual multifunctional initiation sites where activation of all the available carbon-halogen bonds should be feasible.Finally, the introduction of multifunctional initiation sites into CPA precursors must be considerably more efficient than with the contemporary acylation protocols.
Herein, we hypothesize that adducts of trichloroacetyl isocyanate (TAI) can potentially meet all these criteria.TAI is a commercially available in situ derivatizing reagent used in NMR spectroscopy to facilitate structural assignment of compounds bearing hydroxy, [39][40][41][42] thio, 43 and amino 40 groups.In most cases, these moieties undergo rapid, quantitative, and uncomplicated 1,2-addition reactions with TAI, affording carbamate, thiocarbamate, and urea derivatives, respectively.5][46][47][48] Besides 1,2-additions, TAI can take part in other reactions, which increases the diversity of CPA precursors it can modify (Scheme 1a). 39,49We propose here that TAI can be repurposed as a highly efficient vehicle for installing trichloroacetyl groups (TAGs) onto a variety of small-moleculeand macromolecular CPA precursors, avoiding the limitations of the traditional acylation approach.Importantly, several studies used TAG-bearing compounds as initiators for transition metal-catalyzed RDRP of different monomers, 23,24,[50][51][52][53][54] and there is limited evidence that TAGs can act as bi-or trifunctional initiators. 23,536][57][58][59] As visualized in Scheme 1b, the unique combination of TAI reactivity and TAG multifunctionality could effectively amplify the CPA (macro) initiator functionality and provide thus an access to a whole new group of CPAs characterized by dramatically increased chain density and, potentially, new properties and applications.
Scheme 1 (a) Selected reactions of TAI deemed as relevant to polymer chemistry; (b) a scheme contrasting the number of chains installed onto a CPA precursor using the current and the newly proposed (TAI-based) approach.
In this study, we strived to rmly establish the TAI-based Cu-RDRP strategy as a powerful yet simple tool in CPA synthesis.To this end, we investigated and conrmed the considerable universality of TAI-derived initiators by identifying the polymerization conditions under which well-controlled Cu-RDRP of different monomer classes can be achieved.Subsequently, we used 1 H NMR spectroscopy and triple-detection size-exclusion chromatography (TD-SEC) to prove conclusively that the TAIderived TAGs act as inherently trifunctional initiators, which has a profound impact on the topology of the attained polymeric architectures and distinguishes the TAI-based strategy from earlier RDRP approaches.Finally, we provide examples documenting the strong points of the new strategy in various relevant scenarios such as the (one-pot) synthesis of star-shaped and branched CPAs, including a novel "star-on-star" gra copolymer topology, and the modication of otherwise problematic cellulose substrates yielding ultra-high-MW ultra-dense bottle-brush copolymers and diverse surface-graed "2D" and 3D objects with unprecedented ease.

Developing conditions for Cu-RDRP initiated by TAI adducts
In order to probe the universality of TAI-derived initiators, we conducted an extensive screening of multiple polymerization parameters, seeking conditions under which well-controlled Cu-RDRP, characterized by low dispersity and pre-determined MWs of products, can be achieved for monomers from different classes: styrene, acrylates, and methacrylates (Scheme 2).
In the optimization study, we used methyl acrylate (MA), methyl methacrylate (MMA), and styrene as model monomers together with a model initiator, methyl N-trichloroacetyl carbamate (MTAC), that was readily obtained by the addition of TAI into dry methanol, followed by the evaporation of the methanol excess (Scheme 2 and S1 †).We investigated two Cu-RDRP approaches, namely (conventional) atom transfer radical polymerization (ATRP) 26,60 and Cu(0)-mediated RDRP [Cu(0)-RDRP], 61 employing Cu(I) salts (CuBr or CuCl) and Cu(0) (activated copper wire) as catalysts, respectively.Note that Cu(0)-RDRP is sometimes denoted as single-electron transfer living radical polymerization (SET-LRP) 62,63 or supplemental activation reducing agent (SARA) ATRP 64,65 with reference to the expected polymerization mechanism; since we do not address the mechanism in this study, we opted for the generic term Cu(0)-RDRP.Me 6 TREN and PMDETA were used as ligands at different ligand/initiator ratios.Solvents of different polarity were tested to enable future application of the developed strategy to CPA precursors of different solubility.Temperatures ranging from r.t. to 110 °C were utilized depending on the targeted monomer.The monomer/initiator (M/I) ratio of 200 : 1 was used in optimization runs, with other M/I ratios subsequently employed under selected conditions.MW and dispersity values were obtained through size-exclusion chromatography (SEC) calibrated with appropriate standards.
In Table 1, we summarize the selected optimized polymerization conditions for performing MTAC-initiated Cu-RDRP of the model monomers, selected mainly on the basis of achieving high monomer conversion, low dispersity, and a reasonably good match between theoretical and experimental MWs.Numerous additional experimental conditions tested during the extensive screening process are then collected in ESI (Tables S1-S3 †) and might be of use in specic cases, e.g., when a particular ligand/solvent combination is desired.
Our screening showed that MTAC-initiated ATRP (CuBr or CuCl as a catalyst) of MA was largely unsuccessful.Under host of different polymerization conditions, including different solvents, ligands, and temperatures, no polymerization was observed, or the achieved conversions were very low (entries 1-15, Table S1 †).On the other hand, Cu(0)-RDRP catalyzed by Cu wire yielded low-dispersity polymers at high conversion under a range of polymerization conditions, including both polar and non-polar solvents (entries 1-9, Table 1; additional experiments in Table S1 †).SEC elugrams of obtained polymers are provided in Fig. 1 and S3; † a kinetic experiment documenting the good polymerization control is shown in Fig. S4.† Further, we demonstrated that the MTAC initiator works remarkably well for MMA, affording high conversions and lowdispersity products under a range of conditions, including both ATRP and Cu(0)-RDRP methods, different temperatures and solvents of different polarity (entries 10-25, Tables 1 and S2; † for SEC elugrams see Fig. 1 and S5 †).A well-controlled character of the polymerization under the developed conditions was conrmed by kinetic experiments (Fig. S6-S8 †).The high chainend delity of poly(MMA) prepared via MTAC-initiated ATRP in dioxane was demonstrated by chain-extension experiments.To this end, poly(MMA) prepared at high conversion (M n = 9 500, Đ = 1.13; entry 24, Table 1) was successfully used as a macroinitiator to initiate chain-extension with MMA and blockcopolymerization with styrene, which is visualized by clear shis of the corresponding SEC elugrams and the signicant increases in MWs (Fig. S9 †).
Finally, styrene was polymerized at 90 °C through a wellcontrolled Cu(0)-RDRP (in DMSO and toluene) and ATRP (in toluene); however, the process was rather slow (ca.50% conversions reached).High conversions were achieved via ATRP in bulk at 110 °C (entries 26-31, Tables 1 and S3 † for SEC traces see Fig. 1 and S10; † for kinetics see Fig. S11 †).It is of note that Cu(0)-RDRP of styrene in DMSO and DMAc was plagued by gel formation on the copper wire.Such gel formation has been described previously for other Cu(0)-RDRP systems. 62,67,68ollectively, it is rather remarkable that MTAC is able to initiate well-controlled Cu(0)-RDRP of all three studied model monomers in toluene or dioxane because reports on successful Cu(0)-RDRP in non-polar solvents are extremely rare in literature. 66,69,70ext, to verify that the Cu-RDRP conditions established using MTAC are useable also for TAI adducts with other functional groups, we synthesized N,N-diisopropylamine/TAI adduct, 1,1-diisopropyl-3-(2,2,2-trichloroacetyl)-urea (DTAU) (Fig. S12 †).DTAU-initiated Cu-RDRP of styrene, MMA, and MA was then performed under the optimized conditions from our library.The experimental results together with the corresponding SEC traces, collected in Fig. S13, † prove that very similar polymers are obtained irrespective of the linker connecting the initiating TAG fragment to the CPA precursor.This nding suggests that the developed library of Cu-RDRP conditions will be applicable to a variety of CPA precursors bearing TAI-reactive functions.
2][73] To this end, we applied selected conditions to other (meth)acrylates, including functional ones (Table 2 and Fig. S14 †).Although some of the (meth)acrylate analogues (expectedly) did not behave identically as the model monomers, we could easily identify conditions in our library providing well-dened products, which highlights the utility of the extensive screening approach we employed in this study.For example, butyl acrylate (BA) polymerized poorly in toluene (entry 1, Table 2) while quickly affording a well-dened product at quantitative conversion in a bi-phasic system in DMSO (entry 2, Table 2).Similarly, Cu(0)-RDRP of 2-hydroxyethyl methacrylate (HEMA) was uncontrolled in DMSO while affording a well-dened product in dioxane 75 (cf.entries 7 and 8, Table 2).Further, for 2-hydroxyethyl acrylate (HEA), we obtained a well-dened polymer by using a lower ligand loading (cf.entries 3 and 4, Table 2).On the other hand, conditions originally developed for MMA could be directly applied to butyl methacrylate (BMA) and glycidyl methacrylate (GMA) without any changes (entries 5 and 6, Table 2).Taken together, the results conrm the considerable universality of TAI-derived initiators and manifest that our library of optimized conditions (Table 1) can serve as an excellent starting point when polymerizing other (meth)acrylates.
To complement the results on TAG-initiated Cu-RDRP, we also performed a preliminary investigation into the hydrolytic stability of the TAI-derived carbamate linker present in most (macro)initiators used in this study.It can be expected that different TAI-derived linkers, connecting the initiating TAGs with the derivatized precursor, may show different hydrolytic stability/pH sensitivity.0][81][82] To get a preliminary insight, we studied hydrolytic stability of in-chain carbamate linkers in a poly(HEA) star polymer.As shown in Fig. S15 † and in the accompanying discussion, the carbamate linker showed to be considerably resistant to hydrolysis in a wide pH range.1.The noticeable low-MW shoulder in the SEC elugrams of the polymers synthesized at the highest M/I ratios (400 : 1 or 800 : 1) in nonpolar solvents/bulk are ascribed to the products of early termination or competing transfer reactions that tend to be more pronounced when aiming for high-MW products. 66

Functionality of TAI-based initiation groups
The functionality of TAG(s) introduced into CPA precursors by the reaction with TAI represents a key parameter dening the nal polymeric architecture and distinguishes the TAI-based strategy from previous approaches based on monofunctional initiation sites such as BriB.Surprisingly, the functionality of TAG-containing Cu-RDRP initiators has been addressed only rarely in literature.In their seminal paper, Destarac et al. concluded based on NMR data that the studied methyl trichloroacetate acts asat leasta bifunctional initiator in ATRP of styrene. 23Additionally, Lorandi et al. have recently reported that trichloroacetic acid behaves as a trifunctional initiator in ATRP of acrylic acid, 53 maintaining that, upon initiation, the remaining chlorine(s) of the original TAG are increasingly prone to activation (and, subsequently, initiation) due to the penultimate effect. 83Considering these limited previous results, we decided to perform an in-depth investigation into the functionality of the TAI-derived TAGs under our developed polymerization conditions.First, we used 1 H NMR spectroscopy to evaluate the initiator functionality for model low-MW poly(MA), poly(MMA), and polystyrene prepared by MTAC-initiated Cu-RDRP.In the respective spectra, we identied the characteristic signals of the initiator fragment (the -OCH 3 group) and the terminal (chlorine-bearing) and in-chain monomeric units.We then used the relative intensities of these signals, together with the polymer M n value determined by SEC, to calculate initiator functionality, obtaining values close to 3 in all cases (for details see Fig. S17-S19 † and the accompanying discussion).It is of note that the used poly(MMA) sample was obtained at quantitative conversion (entry 23, Table 1), conrming the high endchain delity attained under the used conditions.Overall, our ndings suggest that the MTAC-initiated polymers have the topology of three-arm stars.Consequently, our reported MW values obtained by SEC with relative calibration are slightly underestimated due to the smaller hydrodynamic volume of branched polymers.Additionally, the poly(MMA)-b-polystyrene synthesized above in the chain-extension experiment (Fig. S9 †) should be considered as a 3-arm star with diblock arms.
Next, we wanted to verify that the trifunctionality of TAIderived TAGs is retained also for high-MW CPAs (i.e. a realworld scenario).Since high-MW polymers are not amenable to the simple end-group analysis applied above, we selected a different approach based on the viscometric analysis of the initiation site-related branching using TD-SEC.We reasoned that a standalone TAG provides branching only if the initiator acts as trifunctional while its mono-and bifunctionality leads to a linear polymer.
As model CPAs, we prepared star-shaped poly(MMA) and polystyrene via Cu-RDRP initiated by the pentaerythritol/TAI adduct, pentaerythritol tetrakis((2,2,2-trichloroacetyl) carbamate) (PTAC) (Fig. 2 and S20 †).Using TD-SEC, we then analyzed the parent star polymers as well as the individual TAG-initiated polymeric segments released from the pentaerythritol core via alkaline hydrolysis 33 of carbamate linkers (Fig. 2).As seen from the data summarized in Table S4, † the poly(MMA) star showed low dispersity of 1.21, with the SEC elugram (Fig. 2b) featuring only a small high-MW shoulder, indicating negligible extent of star-star coupling despite the high monomer conversion of 92%.On the other hand, the polystyrene variant was comparatively less well-dened (Đ = 1.69), probably due to the presence of both the coupling products and free segments as suggested by the SEC elugram shape (Fig. 2c).Nevertheless, the low dispersity of the hydrolytically released star segments/arms indicated that well-controlled polymerization was achieved for both monomers.
Fig. 2d and e shows Mark-Houwink (M-H) plots for both the parent multi-arm star polymers and the hydrolytically released segments, alongside the data for broad linear poly(MMA) and polystyrene standards.In addition, the determined M-H a constants, which provide a good measure of polymer branching, are also displayed.While the broad linear standards provided the expected a z 0.6, the considerably lower a value of approximately 0.4 obtained for the released segments conrmed branched character of these polymers and, thus, the TAG trifunctionality. 84Finally, the a values for the parent polymers, presumably 12-arm stars, are even lower (z0.2), as expected for the comparatively denser polymeric architecture. 84ote that we performed also PTAC-initiated polymerization of MA (Table S4 †); however, we were unable to cleanly release the individual segments using our alkaline hydrolysis method in this case.Therefore, in Fig. S21, † we provide only the TD-SEC analysis of the parent star polymer together with the comparison data for a broad linear poly(MA)standard.The same a constant as for the poly(MMA) star above (z0.25)was obtained from the M-H analysis indicating a similar number of star arms and hence TAG trifunctionality also in this case.

Applications of the TAI-based strategy
Having successfully established that TAI functions as an efficient vehicle for introducing universal multifunctional initiation sites into different precursors, we highlight in this section some of the advantages that this new strategy brings to CPA synthesis.
First, we show that the strategy allows for the clean in situ introduction of initiation sites in multi-step protocols without intermediate isolation, which enables the one-pot de novo synthesis of gra copolymers that avoids the isolation/ purication steps typical for standard approaches. 14,32,33To this end, we conducted a three-step protocol depicted in Fig. 3; for experimental details and results see Table S5.† First, we performed a MTAC-initiated copolymerization of HEMA and MMA (20/80 mol%) by Cu(0)-RDRP in dioxane, yielding a well-dened poly(HEMA-co-MMA) copolymer (M n = 23 400, Đ = 1.23) at quantitative conversion (Fig. S22, † top).Subsequently, we in situ modied part of the pendent hydroxyl groups in HEMA units by adding TAI (Fig. S22, † bottom).Finally, upon the addition of another batch of MMA and solvent, we continued the polymerization to yield the nal gra copolymer (Fig. S23 †).Owing to the TAG trifunctionality, the copolymer involves threearm stars graed from a three-arm star backbone, i.e., "star-onstar" architectureapparently a novel type of CPA that structurally represents a hybrid between a star and a gra copolymer.The inated dispersity of the nal product (1.95) is mainly ascribed to the recombination reactions at the macroinitiator preparation stage where quantitative conversion was targeted (a high-MW shoulder in the SEC elugram of the macroinitiator supports this assumption).Nevertheless, TD-SEC analysis showed that the poly(MMA) gras, removed by alkaline hydrolysis, 33 were extremely well dened (Đ = 1.05), indicating a high degree of polymerization control in the graing step.Note that there is a small lower-MW signal in the SEC chromatogram of the star-on-star copolymer.This signal is ascribed to the polymer initiated by the products of TAI reaction with present impurities (e.g., water).The M-H plots provided in Fig. 3 showed a values consistent with the expected topology of three-arm stars (for the macroinitiator precursor and cleaved gras) and with the highly branched nal star-on-star copolymer.Collectively, these results illustrate well that the TAI strategy opens avenues for unconventional approaches to the synthesis of gra and hyper-branched (co)polymers and enables designing of new CPA topologies.
In order to highlight the utility of the TAI-based initiator functionality amplication strategy in the synthesis of previously inaccessible multi-arm star-shaped polymers, we conducted polymerization of MMA initiated by a b-cyclodextrin (b-CD)/TAI adduct (Fig. 4).The adduct was prepared by the reaction of pre-dried b-CD with an excess of TAI whereby the unreacted TAI was quenched with DMSO.The 1 H NMR spectrum of the reaction mixture (Fig. S24 †) conrms the full modication of the b-CD hydroxyl groups as well as the presence of the DMSO/TAI adduct and trichloroacetamide originating from TAI reaction with residual water.The latter two compounds served as low-MW sacricial initiators. 26,33,85The SEC elugrams of the starting b-CD and the b-CD/TAI adduct displayed in Fig. S25a † show a clear shi of the sharp b-CD peak  S4 † for experimental conditions and results.
to higher MWs upon TAI modication.Aerward, the (macro) initiator solution was used to initiate ATRP of MMA in dioxane.Finally, the arms of the isolated star polymer were removed via alkaline hydrolysis for further analysis.
The data shown in Fig. 4, S25b and Table S6 † conrmed that the use of a sacricial initiator represents an efficient strategy 33 for suppressing the formation of intermolecular coupling products (visible as high-MW shoulders in SEC elugrams) even at the almost quantitative monomer conversion reached here.Both the star polymers and cleaved arms/free-growing chains were exceptionally well-dened throughout the polymerization course (Đ = 1.15 and 1.05, respectively, at 96% conversion).Additionally, there was an excellent match in M n and Đ values evaluated for the free-growing chains (the low-MW signal in the SEC of the isolated products) and the mixture of the freegrowing chains and the star arms obtained aer hydrolysis (Table S6 and Fig. S25b †), proving that both the star arms and free chains grew at a similar rate.At the same time, the determined M n values were considerably higher than the theoretical ones calculated from conversion and the MMA/TAI ratio.Collectively, these observations suggest that a part of the TAGs on the b-CD/TAI adduct did not initiate polymerization due to the extreme steric crowding at the TAI-modied b-CD while the remaining TAGs acted as trifunctional initiators, owing to the increased reactivity of the chlorine atoms remaining at TAGs that underwent initiation. 53Nevertheless, a simple comparison of the M n values obtained for the nal multi-arm star polymer and for the arms released therefrom suggests that one b-CD core bears approximately 15 poly(MMA) segments that actually are 3-arm stars on their own.Therefore, the product can be considered as a 45-arm star polymer, highlighting the clear advantage of the new strategy over the previous approaches based on monofunctional initiators that yield, at best, 21 arms from the same precursor in a much more laborious process. 34,37ext, we presumed that the high TAI reactivity will make the new strategy particularly useful in the synthesis of CPAs based on difficult-to-modify substrates.Herein, this is exemplied by the modication of cellulose that has been previously shown to be resistant to the introduction of high concentrations of Cu-RDRP initiation sites using standard acylation protocols. 14,33irst, we studied the reactivity of cellulose (microcrystalline AVICEL PH-101) toward TAI in different solvents.We found that cellulose, dissolved in the traditional cellulose solvent DMAc/ LiCl, 86 could be easily fully modied with a slight excess of TAI (4 eq.toward the anhydroglucose units of cellulose) as documented by the 1 H and 13 C NMR spectra of the isolated adduct (Fig. S26 †).Furthermore, overnight stirring of dioxane-activated cellulose 86 in dioxane containing 4 eq. of TAI led to complete cellulose modication and dissolution.Similarly, the dioxaneactivated cellulose afforded a clear solution of the cellulose/ TAI adduct aer 2 h of reaction with 6 eq. of TAI in THF.Moreover, we found that pre-dried, non-activated cellulose could be fully modied and dissolved when reacted with TAI (6 eq.) in acetonitrile for 4 days.Most importantly, we also revealed that cellulose becomes highly reactive toward TAI when the modication is conducted in DMSO, i.e., a solvent that strongly swells cellulose and increases its accessibility and reactivity. 87When 5 eq. of TAI were added to a suspension of non-dried (or pre-dried and soaked in DMSO overnight) cellulose in DMSO, a clear solution was obtained within 1 min.This nding is remarkable considering the reactivity of TAI toward DMSO and conrms that the modication of substrates in TAIreactive solvents (e.g., DMSO or DMAc), as proposed by Samek et al., 39 is possible also for heterogeneous reactions with polymeric substrates.While we did not focus here on testing the universality of this modication protocol with respect to different cellulose types, we can conrm that the same rapid modication in DMSO was obtained also for a considerably higher-MW cellulose Sigmacell type 101.We thus envisage that this protocol may nd important applications in the eld of cellulose characterization where a similar but considerably more laborious approach based on cellulose modication with phenyl isocyanate is used for cellulose MW determination by SEC. 88ellulose fully modied with TAI represents a unique macroinitiator that can potentially give rise to 9 polymeric chains per one backbone repeat unit, affording, upon gra copolymerization, extremely dense bottle-brush copolymers.To investigate this option, we synthesized a cellulose-gra-poly(-MMA) copolymer via ATRP initiated by a cellulose/TAI adduct (Fig. 5).We rst prepared a stock solution containing the cellulose/TAI adduct and MTAC as a low-MW sacricial initiator by reacting cellulose (AVICEL) with 6 eq. of TAI in acetonitrile and subsequently quenching the excess of TAI by methanol.The TD-SEC analysis of the adduct revealed M n of 106 700 and dispersity of 2.17 consistent with the characteristics of the cellulose precursor (Fig. 5). 86Subsequently, we used the obtained (macro)initiator solution to initiate ATRP of MMA in dioxane.As can be seen from the experimental data collected in Table S7, † 27% conversion was reached in 5 h, which corresponds to the M n (theor.) of 9 644 000, as calculated from the macroinitiator number-average degree of polymerization (DP n ) of 147, assuming three TAI-modied hydroxyl groups per a repeat unit that initiate polymerization.Aer 24 h, 72% conversion was attained, corresponding to M n (theor.) of 25 539 000.In this context, it is rather remarkable how the application of  S6. † a sacricial initiator effectively suppresses intermolecular crosslinking reactions even for such an ultra-dense bottle-brush at very high monomer conversion. 33t is known that SEC of high-MW bottle-brushes is challenging due to the non-SEC elution behavior of high-MW fractions. 16,89Indeed, we observed delayed elution of high-MW polymer fraction(s), which obscured the MW analysis (for details see Fig. S27 † and the accompanying discussion).Nevertheless, for the 5 h sample, we were able to obtain, using universal calibration, rather realistic M n of 28 300 for the freegrowing chains initiated by the sacricial initiator (Table S7 †).This value agreed well with that for the mixture of gras and free-growing chains acquired through the alkaline hydrolysis of the isolated product (M n = 24 400), conrming that the polymer grew at a similar rate from both the cellulose backboneattached and free initiation sites.The close match between the experimental M n values and the M n (theor.),calculated based on the monomer conversion and the MMA/TAG ratio (considering all forms of TAI adducts), indicates that the much lower than theoretical M n of the gra copolymer determined by TD-SEC (3 174 000) is severely underestimated due to the effects discussed above.The high compactness of the prepared bottlebrush copolymer is well-illustrated by the low a constant obtained from the M-H plot (Fig. 5).Further, even though we were unable to obtain any MW values from the TD-SEC analysis of the 24 h sample, we note that a good match between the M n (theor.)and M n (SEC) values of the hydrolysis product was retained also in this case (Table S7 †).Additionally, the unimodal character of the SEC signals (data not shown) together with the low obtained Đ of 1.11 suggested that the M n of gras was similar as that determined for the hydrolysate.Altogether, the obtained data point to the extreme MW of the nal cellulose-gra-poly(MMA) copolymer despite the rather low-MW cellulose backbone employed.We predict that truly giant cellulose-based gra copolymers with MWs in the order of hundreds of millions should be readily accessible using this strategy when starting from regular cellulose substrates having MWs in hundreds of thousands.
In the last part of this study, we highlight that the use of TAIderived multifunctional initiation groups can have a much broader impact in the cellulose eld as it can be easily adapted for the surface modication of diverse cellulose-based precursors.In the rst example, we took advantage of the extremely high reactivity of DMSO-swollen cellulose toward TAI to demonstrate the possibility of spatial control in surfaceinitiated (SI) graing from at cellulose/TAI substrates.To this end, we placed a DMSO-wetted cellulose lter paper (Whatman) into a metallic mask and applied TAI into the mask opening.We then used the puried TAI-modied paper to initiate ATRP of MMA, obtaining within 30 min a thick, macroscopic layer of polymer bound to the regions of the paper surface originally exposed to TAI (Fig. 6).Notably, there was  S7. † virtually no polymer growth from the rear side of the paper, conrming the instantaneous TAI reaction with the DMSOwetted paper.We thus envisage that this strategy could be applicable to the fabrication of Janus-type fabrics. 90n another experiment, 5 cm of a thick cotton thread was surface-modied with TAI in DMSO and subsequently used to trigger MMA polymerization, which led to the complete coverage of the thread with a thick polymer layer (Fig. 7 and S28 †).In the close-up picture, the disentanglement of the individual strands at the thread ends and the efficient modication of the smallest thread features is well-visible.Finally, to illustrate the feasibility of this strategy also for more complex (cellulose-based) natural substrates, we successfully graed a polymer layer from TAI-modied pine tree cone in the same way (Fig. 7 and S29 †).The non-modied areas visible on the cone scales correspond to the places where seeds blocked the access of TAI during the modication step (the seeds got released during the polymerization step).This further demonstrates the spatial control in the TAI-based SI graing strategy.Altogether, these preliminary results show the great potential of the TAI-based strategy in both homogeneous and heterogeneous SI graing from natural polymeric substrates with efficiency and graing density unparalleled by the traditional protocols. 30,91

Conclusions
In conclusion, we showed in this study that the application of universal multifunctional TAI-based Cu-RDRP initiation sites can signicantly extend the "toolset" of synthetic polymer chemists aspiring at constructing CPAs of novel architectures and properties.To assist with this task, we provided here an extensive library of optimized conditions for conducting wellcontrolled TAG-initiated Cu-RDRP of different monomers.The unique synergistic combination of TAI trifunctionality and extreme reactivity allows for rapid amplication of the functionality of CPA precursor-derived (macro)initiators.As a result, an unprecedently high number of polymeric chains can be easily installed onto CPA precursors, in stark contrast to earlier approaches based on monofunctional initiation sites introduced into precursors via inefficient acylations.Resulting opportunities in CPA synthesis were illustrated on multiple relevant scenarios yielding CPAs of novel qualities in uncomplicated protocols.We envisage that in future the scope of the presented strategy will be signicantly extended.For example, the broad reactivity of TAI will extend the range of functional substrates that could serve as CPA precursors; moreover, the different reactivity (stability) of linkers through which precursors are connected to the initiating TAGs could be exploited in programmed CPA decomposition.Furthermore, synthesis of miktoarm star polymers based on telechelic precursors or preparation of ultra-dense polymeric brushes with controlled thickness 92 represent some of the expected future applications.Last but not least, the study of the physico-chemical properties of the new multi-chain CPAs can be desirable from the viewpoint of future applications of these materials.

Fig. 1
Fig.1SEC elugrams of selected polymers prepared by MTAC-initiated Cu-RDRP at different M/I ratios.Product characteristics are provided in Table1.The noticeable low-MW shoulder in the SEC elugrams of the polymers synthesized at the highest M/I ratios (400 : 1 or 800 : 1) in nonpolar solvents/bulk are ascribed to the products of early termination or competing transfer reactions that tend to be more pronounced when aiming for high-MW products.66

Fig. 2
Fig. 2 TAG functionality study: general scheme of the synthesis of model multi-arm stars based on a pentaerythritol core (a); elugrams -RI traces (b and c) and M-H plots (d and e) from the TD-SEC analysis of the synthesized poly(MMA) (b and d) and polystyrene (c and e) multi-arm star polymers and of products of their alkaline hydrolysis.Data for broad linear poly(MMA) and polystyrene standards are shown for comparison.See TableS4† for experimental conditions and results.

Fig. 4
Fig. 4 Synthesis of multi-arm poly(MMA) stars through ATRP initiated by the b-CD/TAI adduct.(Top) General reaction scheme; (bottom) TD-SEC analysis (elugrams -RI traces) of samples taken at different polymerization stages.Experimental details are provided in TableS6.†

Fig. 5
Fig.5Synthesis of the ultra-dense bottle-brush cellulose-g-poly(MMA) graft copolymer via ATRP of MMA initiated by the cellulose/TAI adduct.(Top) General reaction scheme; (bottom) TD-SEC analysis (left -RI elugrams; right -M-H plots) of the cellulose/TAI macroinitiator, the copolymer obtained after 5 h, and poly(MMA) obtained after alkaline hydrolysis of the isolated product.Experimental details are provided in TableS7.†

Fig. 6
Fig. 6 Spatial control in the modification of Whatman filter paper with TAI and subsequent ATRP SI grafting of MMA from the modified cellulose surface.

Fig. 7 A
Fig. 7 A cotton thread (top) and a pine tree cone (bottom) grafted with poly(MMA) via the two step TAI-modification/ATRP-grafting strategy.

Table 1
Selected optimized conditions for MTAC-initiated Cu-RDRP of model monomers a